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A comprehensive one-dimensional kinetic model was developed to detail ammonia oxidation and nitrous oxide (N2O) formation on a dual-layer ammonia slip catalyst (ASC).

Protein kinases C (PKCs) are a family of serine/threonine kinases involved in various cellular processes, including proliferation, differentiation, cell survival, and apoptosis. Here, we report the identification, structure-activity relationship (SAR), and 3D-QSAR studies of 69 natural indolocarbazoles, including 15 new compounds, from marine streptomyces strains. Interestingly, we found that the chair conformational isomer of 7-oxo-staurosporine (compound 15) inhibited PKCθ more potently than the corresponding boat isomer. An evaluation of kinase selectivity and antitumor efficacy revealed that 15 was a potent dual PKCθ/δ inhibitor and that it could efficiently inhibit tumor growth in pancreatic cancer (PC) by inducing cellular apoptosis and suppressing the NF-κB/p-P65 pathway. In addition, we demonstrated that overexpression of p-PKCδ and p-P65 was associated with poor survival rates in patients with PC, and p-PKCθ expression also showed significant positive correlations with p-PKCδ and p-P65 levels. Finally, the PC patient-derived xenograft model further confirmed the potential anti-PC efficacy of 15.

Gastric cancer (GC) is the third leading cause of cancer-related death. Although the therapeutic approaches have improved, the 5-year survival rate of GC patients after surgical resection remains low due to the high rates of metastasis and recurrence. Patients with schizophrenia have significantly lower incidences of cancer after long-term drug treatment, suggesting the potential or partially ameliorate the risk of cancer development of antipsychotic drugs. The goal of this study was to explore antipsychotic drugs with an optional effective therapy against gastric cellular carcinoma. We found that sertindole, an atypical antipsychotic, exhibited anti-tumor efficacy on human GC cells in vitro and in vivo. Moreover, sertindole in combination with cisplatin dramatically enhanced apoptosis-induction in GC cells. In addition, the pro-apoptotic effect of sertindole on GC might in part, involved in inhibition of STAT3 activation and downstream signals, including Mcl1, surviving, c-Myc, cyclin D1. Collectively, these results suggested that sertindole could be a potential anticancer reagent and be an attractive therapeutic adjuvant for the treatment of human GC.

The secretory output of cell-cell interfaces must be tightly controlled in space and time to ensure functional efficacy. This is particularly true for the cytotoxic immune synapse (IS), the stereotyped junction formed between a cytotoxic lymphocyte and the infected or transformed target cell it aims to destroy1. Cytotoxic lymphocytes kill their targets by channeling a mixture of granzyme proteases and the pore forming protein perforin directly into the IS2, 3. The synaptic secretion of these toxic molecules constrains their deleterious effects to the target cell alone, thereby protecting innocent bystander cells in the surrounding tissue from collateral damage. Despite the importance of this process for immune specificity, the molecular and cellular mechanisms that establish secretory sites within the IS remain poorly understood. Here, we identified an essential role for integrin mechanotransduction in cytotoxic secretion using a combination of single cell biophysical measurements, ligand micropatterning, and functional assays. Upon ligand-binding, the αLβ2integrin LFA-1 functioned as a spatial cue, attracting lytic granules containing perforin and granzyme and inducing their fusion at closely adjacent sites within the synaptic membrane. LFA-1 molecules were subjected to pulling forces within these secretory domains, and genetic or pharmacological suppression of these forces abrogated cytotoxicity. We conclude that lymphocytes employ an integrin-dependent mechanical checkpoint to enhance both the potency and the security of their cytotoxic output.

Dysregulated crosstalk between different signaling pathways contributes to tumor development, including resistance to cancer therapy. In the present study, we found that the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib failed to suppress the proliferation of PANC-1 and MGC803 cells by activating the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, while the JAK2 inhibitor fedratinib failed to inhibit the growth of the PANC-1 cells upon stimulation of extracellular signal-regulated kinase (ERK) signaling. In particular, the most prominent enhancement of the anti-proliferative effect resulted from the concurrent blockage of the JAK2/STAT3 and ERK signaling pathways. Furthermore, the combination of the two inhibitors resulted in a reduced tumor burden in mice. Our evidence suggests novel crosstalk between JAK2/STAT3 and ERK signaling in gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC) cells and provides a therapeutic strategy to overcome potential resistance in gastrointestinal cancer.

Designing and developing a cost-effective and highly stable hydrogen evolution reaction (HER) electrocatalyst under alkaline conditions is critical for sustainable energy conversion and storage. Cobalt-based oxides have been considered as ideal HER electrocatalysts and have been intensively studied; however, their catalytic activity is still unsatisfactory. The modulation of electrical conductivity, which limits the catalytic activity of the transition metal cobalt-based oxides, is an effective way to improve the electron transfer efficiency, mass transfer and kinetic process of the HER. Herein, an ultrathin carbon layer coated cobalt(II) oxide nanosheet array grown in situ on carbon cloth was synthesized by a simple two-step method for efficient HER. The obtained interconnected C@CoO nanosheet array possesses lower overpotentials and smaller Tafel slopes than those of bare CoO and shows excellent stability in 20 h long-term stability tests. The ultrathin carbon coated structure provides CoO with enhanced electron transfer efficiency, increased number of active sites and strong structural stability. This work paves an interesting route for boosting the HER performance of oxide-based electrocatalysts through introducing an ultrathin carbon coating for various energy systems in the future.

The exploration of high-performance, cost-effective, and stable electrocatalysts for the oxygen evolution reaction (OER) is crucial for future energy storage and conversion technologies. Cobalt-based hydroxides and oxides have been considered as ideal OER electrocatalysts and have been intensively studied; however, their catalytic activity is still unsatisfactory. It is known that the interfacial electron and structure engineering of composite electrocatalysts often results in synergistically enhanced catalytic performance. Herein, a self-supported binary heterogeneous catalyst composed of CoFe LDH/Co0.85Se nanosheet arrays vertically grown on carbon cloth has been reported. The heterostructure electrocatalyst exhibits excellent activity for the OER in alkaline electrolyte, requiring an overpotential of only 241 mV at a current density of 10 mA cm−2 with a small Tafel slope of 48 mV dec−1. These performances are significantly better than those of the bare CoFe LDH and Co0.85Se catalysts. Moreover, the composite electrodes exhibit outstanding durability within 40 h of testing. Our further electrochemical results show that the excellent activities of the heterostructure electrodes should be ascribed to the interfacial coupling effect, increased number of activity sites, accelerated electron transfer, and strong structural stability. This work paves an interesting route for boosting the OER performance of oxide-based electrocatalysts by the regulation of electronic structure through introducing non oxide electrocatalysts for various applications.

To overcome the drawback of UV light response in La2Ti2O7 nanosheets, novel up-conversion carbon quantum dots (CQDs) with visible light response have been introduced on the surface of La2Ti2O7 for efficient enhancement of photocatalytic performance. The resulted CQDs/La2Ti2O7 samples were characterized by XRD, TEM, FT-IR, XPS and UV–vis, respectively. Rhodamine B (RhB) solution was chosen as the target organic pollutant to evaluate the photocatalytic activity under visible light irradiation. The results indicated that 5 wt% loading of CQDs composite exhibited the best performance. Both the up-converted photoluminescence behavior and their electron capturing ability of CQDs are considered as the main reasons for the enhanced photocatalytic abilities.

Developing low-cost, high performance, stable non-noble bifunctional electrocatalysts for overall water splitting is of great importance for future energy supplement. Despite recent advances in the synthesis of transition metal selenide nanostructures, the fabrication of porous nanosheet based binder-free electrode with more active sites remains a major challenge. Herein, the self-templating construction of a porous CoSe2 nanosheet array on carbon cloth (p-CoSe2/CC) has been reported by vapor selenizing the preprepared α-Co(OH)2 nanosheet array precursor. Arising from large active surface area, fast diffusion of generated gas and strong structural stability, the as-obtained p-CoSe2/CC can serve as an efficient bifunctional electrocatalyst for both OER and HER in alkaline electrolyte, with a current density of 10 mA cm–2 at overpotential of 243 mV for OER and 138 mV for HER, respectively. Moreover, when p-CoSe2/CC is assembled as an alkaline electrolyzor, it only needs a cell voltage of 1.62 V at 10 mA cm–...

In this paper, we took the initiative to investigate the synthesis and photocatalytic properties of new solar-light active Ag3PO4/La2Ti2O7 0D/2D heterojunction photocatalysts with 10 wt% ∼70 wt% Ag3PO4 loading. 2D La2Ti2O7 nanosheets modified by uniformly dispersed super-small Ag3PO4 nanoparticles with average particle size as small as 4.9 nm were prepared by an in-situ chemical deposition method, and probed by electron microscopy, X-ray diffraction and UV–vis diffuse reflection spectroscopy. The photocatalytic activities were evaluated using Rhodamine B (RhB) as a target organic pollutant under simulated solar light irradiation. The results show that La2Ti2O7 nanosheets modified with proper amount of Ag3PO4 nanoparticles exhibited much higher photocatalytic activity. The optimal loading amount of Ag3PO4 was observed to be 50 wt% with the best photocatalytic performance, which could degrade almost all RhB dyes within 8 min under sunlight irradiation with the highest rate constant value of 0.5632 min−1. The mechanism accounting for the photocatalytic results were also proposed by PL, transient photocurrent response, radical trapping experiments and electron paramagnetic resonance spectra. Moreover, the photocorrosion of Ag3PO4/La2Ti2O7 photocatalysts is efficiently suppressed after depositing thin layers of AgI on Ag3PO4 nanoparticles.

Cells have the remarkable ability to sense the mechanical stiffness of their surroundings. This has been studied extensively in the context of cells interacting with planar surfaces, a conceptually elegant model that also has application in biomaterial design. However, physiological interfaces are spatially complex, exhibiting topographical features that are described over multiple scales. This report explores mechanosensing of microstructured elastomer surfaces by CD4 + T cells, key mediators of the adaptive immune response. We show that T cells form complex interactions with elastomer micropillar arrays, extending processes into spaces between structures and forming local areas of contraction and expansion dictated by the layout of microtubules within this interface. Conversely, cytoskeletal reorganization and intracellular signaling are sensitive to the pillar dimensions and flexibility. Unexpectedly, these measures show different responses to substrate rigidity, suggesting competing processes in overall T cell mechanosensing. The results of this study demonstrate that T cells sense the local rigidity of their environment, leading to strategies for biomaterial design.

Immunological synapse formation between cytotoxic T lymphocytes (CTLs) and the target cells they aim to destroy is accompanied by reorientation of the CTL centrosome to a position beneath the synaptic membrane. Centrosome polarization is thought to enhance the potency and specificity of killing by driving lytic granule fusion at the synapse and thereby the release of perforin and granzymes toward the target cell. To test this model, we employed a genetic strategy to delete centrioles, the core structural components of the centrosome. Centriole deletion altered microtubule architecture, as expected, but surprisingly had no effect on lytic granule polarization and directional secretion. Nevertheless, CTLs lacking centrioles did display substantially reduced killing potential, which was associated with defects in both lytic granule biogenesis and synaptic actin remodeling. These results reveal an unexpected role for the intact centrosome in controlling the capacity, but not the specificity, of cytotoxic killing.

Cytotoxic T lymphocytes (CTLs) kill by forming immunological synapses with target cells and secreting toxic proteases and the pore forming protein perforin into the intercellular space. Immunological synapses are highly dynamic structures that boost perforin activity by applying mechanical force against the target cell. Here, we employed high-resolution imaging and microfabrication to investigate how CTLs exert synaptic forces and coordinate their mechanical output with perforin secretion. Using micropatterned stimulatory substrates that enable synapse growth in three dimensions, we found that perforin release occurs at the base of actin-rich protrusions that extend from central and intermediate locations within the synapse. These protrusions, which depended on the cytoskeletal regulator WASP and the Arp2/3 actin nucleation complex, were required for synaptic force exertion and efficient killing. They also mediated physical deformation of the target cell surface during CTL-target cell interactions. Our results reveal the mechanical basis of cellular cytotoxicity and highlight the functional importance of dynamic, three-dimensional architecture in immune cell-cell interfaces.

Given the poor prognosis of unresectable advanced gastric cancer (GC), novel therapeutic strategies are needed. The mitogen-activated protein kinase (MAPK) signaling cascade, the most frequently activated pathway in GC, plays an important role in tumorigenesis and metastasis. The MAPK/extracellular signal-regulated kinase (ERK) pathway is an attractive therapeutic target for GC. In this study, trametinib, a mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor, reduced the p-ERK level and significantly increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in GC cells, resulting in reduced sensitivity to trametinib. Physapubescin B (PB), a steroidal compound extracted from the plant Physalis pubescens L., inhibited the proliferation and induced the apoptosis of GC cells by suppressing STAT3 phosphorylation. The combination of PB and trametinib suppressed the STAT3 phosphorylation induced by trametinib, and synergistically suppressed gastric tumor growth in vitro and in vivo. Together, these results indicate that inhibition of both MEK and STAT3 may be effective for patients with MAPK/ERK pathway-addicted GC.

The immunological synapse formed between a cytotoxic T lymphocyte (CTL) and an infected or transformed target cell is a physically active structure capable of exerting mechanical force. Here, we investigated whether synaptic forces promote the destruction of target cells. CTLs kill by secreting toxic proteases and the pore forming protein perforin into the synapse. Biophysical experiments revealed a striking correlation between the magnitude of force exertion across the synapse and the speed of perforin pore formation on the target cell, implying that force potentiates cytotoxicity by enhancing perforin activity. Consistent with this interpretation, we found that increasing target cell tension augmented pore formation by perforin and killing by CTLs. Our data also indicate that CTLs coordinate perforin release and force exertion in space and time. These results reveal an unappreciated physical dimension to lymphocyte function and demonstrate that cells use mechanical forces to control the activity of outgoing chemical signals.

This paper presents a novel strategy to enhance the mechanical properties of a solid catalyst. By employing a slip-casting method, an alumina membrane can be prepared on the surface of activated carbon particles uniformly. Significantly, the mechanical properties test indicates that the attrition index of activated carbon decreases from 12.6% to 2.9% due to the alumina membrane coating.

Cytotoxic T lymphocytes (CTLs) kill by forming immunological synapses with target cells and secreting toxic proteases and the pore forming protein perforin into the intercellular space. Immunological synapses are highly dynamic structures that potentiate perforin activity by applying mechanical force against the target cell. Here, we employed high-resolution imaging and microfabrication to investigate how CTLs exert synaptic forces and coordinate their mechanical output with perforin secretion. Using micropatterned stimulatory substrates that enable synapse growth in three dimensions, we found that perforin release occurs at the base of actin-rich protrusions that extend from central and intermediate locations within the synapse. These protrusions, which depended on the cytoskeletal regulator WASP and the Arp2/3 actin nucleation complex, were required for synaptic force exertion and efficient killing. They also mediated physical distortion of the target cell surface during CTL-target cell interactions. Our results reveal the mechanical basis of cellular cytotoxicity and highlight the functional importance of dynamic, three-dimensional architecture in immune cell-cell interfaces.One sentence summaryCytotoxic T lymphocytes use F-actin-rich protrusions at the immunological synapse to potentiate perforin-and granzyme-mediated target cell killing.

The vast osteocytic network is believed to orchestrate bone metabolic activity in response to mechanical stimuli through production of sclerostin, RANKL, and osteoprotegerin (OPG). However, the mechanisms of osteocyte mechanotransduction remain poorly understood. We’ve previously shown that osteocyte mechanosensitivity is encoded through unique intracellular calcium (Ca2+) dynamics. Here, by simultaneously monitoring Ca2+ and actin dynamics in single cells exposed to fluid shear flow, we detected actin network contractions immediately upon onset of flow-induced Ca2+ transients, which were facilitated by smooth muscle myosin and further confirmed in native osteocytes ex vivo. Actomyosin contractions have been linked to the secretion of extracellular vesicles (EVs), and our studies demonstrate that mechanical stimulation upregulates EV production in osteocytes through immunostaining for the secretory vesicle marker Lysosomal-associated membrane protein 1 (LAMP1) and quantifying EV release in conditioned medium, both of which are blunted when Ca2+ signaling was inhibited by neomycin. Axial tibia compression was used to induce anabolic bone formation responses in mice, revealing upregulated LAMP1 and expected downregulation of sclerostin in vivo. This load-related increase in LAMP1 expression was inhibited in neomycin-injected mice compared to vehicle. Micro-computed tomography revealed significant load-related increases in both trabecular bone volume fraction and cortical thickness after two weeks of loading, which were blunted by neomycin treatment. In summary, we found mechanical stimulation of osteocytes activates Ca2+-dependent contractions and enhances the production and release of EVs containing bone regulatory proteins. Further, blocking Ca2+ signaling significantly attenuates adaptation to mechanical loading in vivo, suggesting a critical role for Ca2+-mediated signaling in bone adaptation., How bone grows in response to loading People gain bone in response to exercise and lose it during prolonged bedrest; now we’re closer to understanding how this happens. Bone cells called osteocytes act as mechanical sensors, responding to changes in force by regulating the activity of bone-forming osteoblasts and bone- resorbing osteoclasts. X. Edward Guo at Columbia University in New York and colleagues had previously shown that osteocytes exhibit oscillations in intracellular calcium in response to mechanical stimulation, but the downstream effects of this had been unclear. Using multiple approaches, they have now shown that the cytoskeleton contracts in response to these oscillations, in turn triggering the production and release of extracellular vesicles containing bone-regulatory proteins. When calcium signaling was blocked, vesicle production and release was blunted, and mice failed to show the normal increase in bone formation in response to mechanical loading.

UV Resistance Locus 8 (UVR8), an ultraviolet-B (UV-B; 280–315 nm) photoreceptor, participates in the regulation of various plant growth and developmental processes. UV-B radiation is an important factor enhancing the production of active components in medicinal plants. To-date, however, studies on UV-B photoreceptors have largely focused on Arabidopsis, and the functions of UVR8 in medicinal plants are still largely unknown. In the present study, a homolog of Arabidopsis UVR8, CmUVR8, was isolated from Chrysanthemum morifolium Ramat, and its structure and function were analyzed in detail. Protein sequence analysis showed that CmUVR8 contained nine conserved regulators of chromosome condensation 1 repeats, seven conserved bladed propellers, one C27 region, three “GWRHT” motifs and several crucial amino acid residues (such as 14 Trps and 2 Args), similar to AtUVR8. 3-D structural analysis of CmUVR8 indicated that its structure was similar to AtUVR8. Heterologous expression of CmUVR8 could rescued the deficient phenotype of uvr8-6, a mutant of UVR8 in Arabidopsis, indicating the role of CmUVR8 in the regulation of hypocotyl elongation and HY5 gene expression under UV-B irradiation. Moreover, CmUVR8 regulates UV-B-induced expression of four flavonoids biosynthesis-related genes and the UV-B-induced accumulation of flavonoids. Furthermore, the interaction between CmUVR8 and CmCOP1 were confirmed using a yeast two-hybrid assay. These results indicated that CmUVR8 plays important roles in UV-B signal transduction and the UV-B-induced accumulation of flavonoids, as a counterpart of AtUVR8.

Recent insights into the importance of mechanosensing and force transmission at the immune synapse have spurred increased interest in the mechanical properties of leukocyte cell-cell interactions. In this chapter, we describe an imaging-based strategy for measuring cellular forces that utilizes optically transparent arrays of flexible micropillars. This approach has several distinct advantages over standard traction force microscopy, and we anticipate that it will prove very useful for investigators who wish not only to quantify ligand-induced forces with high spatiotemporal resolution but also to place those forces within the context of a broader cell biological response.

Recent insights into the importance of mechanosensing and force transmission at the immune synapse have spurred increased interest in the mechanical properties of leukocyte cell-cell interactions. In this chapter, we describe an imaging-based strategy for measuring cellular forces that utilizes optically transparent arrays of flexible micropillars. This approach has several distinct advantages over standard traction force microscopy, and we anticipate that it will prove very useful for investigators who wish not only to quantify ligand-induced forces with high spatiotemporal resolution but also to place those forces within the context of a broader cell biological response.

Background Because of its rough surface and the hydrophobic property of porous activated carbon (AC) particles, it is more difficult to grow a zeolite layer on an AC surface than on metal oxides. The aim of the present study is the in situ hydrothermal synthesis of continuous ZSM-5 zeolite layer encapsulated porous AC particles (AC@ZSM-5) through an alumina intermediate layer strategy. To evaluate the effects of the zeolite layer on its catalytic application, active species (Co and Zr) were introduced into the AC and used for Fischer–Tropsch synthesis. Results A continuous zeolite layer cannot be formed on the surface of the irregular AC particles, even when pretreated by air oxidation or concentrated nitric acid, but can be synthesized using the alumina intermediate layer method. A catalytic test of CoZr/AC@ZSM-5 indicates that the zeolite layer shell has a marked effect on product distributions. Conclusion Aided by the alumina intermediate layer, zeolite crystals nucleate at the support/solution interface rather than in solution. For Fischer–Tropsch synthesis over CoZr/AC@ZSM-5, the product distributions are shifted to methane and light hydrocarbon compared with that of CoZr/AC. © 2013 Society of Chemical Industry

The sorption properties of SBA-15 and MCM-41 for toluene and ethyl acetate were investigated by temperature programmed desorption (TPD) techniques and an analysis of breakthrough curves. The amount of toluene adsorbed onto SBA-15 was distinctly larger than that onto MCM-41, while the desorption temperature of toluene from the former was also higher than that from MCM-41. However, in the case of ethyl acetate, similar adsorption and desorption behaviours were observed on these two samples. The interaction between organic molecules and adsorbents was evaluated in terms of the affinity index. It was found that both SBA-15 and MCM-41 exhibited positive adsorption properties towards ethyl acetate but negative behaviours towards toluene. Compared to the MCM-41, the larger quantity of toluene retained by SBA-15 and the higher desorption temperature for toluene relative to MCM-41 were ascribed to the higher adsorption potential existing in the secondary pores of SBA-15.

Microhemorrhages are common in the aging brain, and their incidence is correlated with increased risk of neurodegenerative disease. Past work has shown that occlusion of individual cortical microvessels as well as large-scale hemorrhages can lead to degeneration of neurons and increased inflammation. Using two-photon excited fluorescence microscopy in anesthetized mice, we characterized the acute and chronic dynamics of vessel bleeding, tissue compression, blood flow change, neural degeneration, and inflammation following a microhemorrhage caused by rupturing a single penetrating arteriole with tightly-focused femtosecond laser pulses. We quantified the extravasation of red blood cells (RBCs) and blood plasma into the brain and determined that the bleeding was limited by clotting. The vascular bleeding formed a RBC-filled core that compressed the surrounding parenchymal tissue, but this compression was not sufficient to crush nearby brain capillaries, although blood flow speeds in these vessels was reduced by 20%. Imaging of cortical dendrites revealed no degeneration of the large-scale structure of the dendritic arbor up to 14 days after the microhemorrhage. Dendrites close to the RBC core were displaced by extravasating RBCs but began to relax back one day after the lesion. Finally, we observed a rapid inflammatory response characterized by morphology changes in microglia/macrophages up to 200 µm from the microhemorrhage as well as extension of cellular processes into the RBC core. This inflammation persisted over seven days. Taken together, our data suggest that a cortical microhemorrhage does not directly cause significant neural pathology but does trigger a sustained, local inflammatory response.